Myeloproliferative neoplasms (MPN) are an incompletely understood group of diseases caused by abnormalities in the bone marrow stem cells leading to an accumulation of an excess of blood cells. A small number of key genetic mutations have been identified that drive the bone marrow stem cells to divide in an unregulated fashion and play a role in the development of MPNs. The clinical picture and prognosis of MPN varies widely, however, and in some patients no known genetic mutation can be identified. These findings suggest that additional unknown genetic abnormalities act together to contribute to the development of MPNs. Over the last several years, studies in our laboratory have focused on identifying and understanding additional genetic changes that contribute to the development and progression of MPNs. Recently, mutations in a previously undefined gene, TET oncogene family member-2 (TET2) has been identified in a subset of patients with MPNs, as well as patients with other diseases of the blood. The function of this gene is unknown. It may be acting as a tumor suppressor gene, which is a gene that regulates cell growth and survival. When a tumor suppressor gene is mutated and cannot function, then the cells grow without regulation. The proposed work is based on the hypothesis that mutation of TET2 plays a role in the development of MPNs, and that understanding the function will allow this gene to be used as a potential target for therapy or as an aid in diagnosis. Our goal is to study the function of this gene in the development of normal blood cells and cancer blood cells. To study the function of TET2 this gene will be manipulated in cells from human bone marrow. Aim 1 is to determine if the TET2 protein plays a role in controlling the development and growth of blood cells. The genetic mutations found in patients will be reproduced to see if the mutations alter the function of TET2. Aim 2 is to determine if TET2 acts to modify other genes and affects how those genes function. These studies will contribute to the understanding of the role of this potential tumor suppressor gene in the development of MPNs. MPNs are difficult to diagnose and to treat, and an increased understanding of the underlying genetic abnormalities will allow for improved diagnosis and targeted therapy design. PUBLIC HEALTH RELEVANCE: Successful completion of this study will identify the function of the gene TET2 in hematopoiesis and its role in the development of myeloid cancers. Only when the function of a gene's product is understood can that pathway be accurately targeted to treat or prevent cancer development. Understanding the effects of TET2 in hematopoiesis and cancer development will help identify therapeutic targets for epigenetic modifying therapies in myeloid malignancies, potentially decreasing the side effects of therapy and the risk of secondary cancers in patients.